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O-GlcNAcylation of NF-κB Promotes Lung Metastasis of Cervical Cancer Cells via Upregulation of CXCR4 Expression

  • Ali, Akhtar (Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University, School of Medicine) ;
  • Kim, Sung Hwan (Department of Thoriac and Cardiovascular Surgery, Gyeongsang National University, School of Medicine) ;
  • Kim, Min Jun (Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University, School of Medicine) ;
  • Choi, Mee Young (Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University, School of Medicine) ;
  • Kang, Sang Soo (Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University, School of Medicine) ;
  • Cho, Gyeong Jae (Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University, School of Medicine) ;
  • Kim, Yoon Sook (Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University, School of Medicine) ;
  • Choi, Jun-Young (Department of Thoriac and Cardiovascular Surgery, Gyeongsang National University, School of Medicine) ;
  • Choi, Wan Sung (Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University, School of Medicine)
  • Received : 2017.05.31
  • Accepted : 2017.06.05
  • Published : 2017.07.31

Abstract

C-X-C chemokine receptor 4 (CXCR4) stimulates cancer metastasis. NF-${\kappa}B$ regulates CXCR4 expression in cancer cells, and O-GlcNAc modification of NF-${\kappa}B$ promotes its transcriptional activity. Here, we determined whether CXCR4 expression is affected by O-GlcNAcylation of NF-${\kappa}B$ in lung metastasis of cervical cancer. We found elevated levels of O-linked-N-actylglucosamine transferase (OGT) and O-GlcNAcylation in cervical cancer cells compared to those in non-malignant epithelial cells and detected increased expression of NF-${\kappa}B$ p65 (p65) and CXCR4 in cervical cancer cells. Knockdown of OGT inhibited the O-GlcNAcylation of p65 and decreased CXCR4 expression levels in HeLa cells. Thiamet G treatment increased O-GlcNAcylated p65, which subsequently enhanced CXCR4 expression levels. Inhibition of O-GlcNAcylation by 6-Diazo-5-oxo-L-norleucine (DON) treatment decreased p65 activation, eventually inhibiting CXCR4 expression in HeLa cells. Lung tissues from mice engrafted with OGT-knockdown HeLa cells (shOGT) exhibited lower expression of Ki-67 and HPV E6 and E7 oncogenes compared to lung tissues from mice engrafted with control HeLa cells (shCTL). In addition, lung tissues from mice engrafted with shOGT cells exhibited lower p65 and CXCR4 immunoreactivity compared to tissues from mice engrafted with shCTL cells. Taken together, our data suggest that p65 O-GlcNAcylation promotes lung metastasis of cervical cancer cells by activating CXCR4 expression.

Acknowledgement

Supported by : National Research Foundation of Korea

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